1,1-bis(trifluoromethyl)-2,2-diphenylethylenes having selected substituents on phenyl

ABSTRACT

Described are certain 1,1-bis(trifluoromethyl)-2,2diphenylethylenes, which carry an oxy group in the para position of at least one benzene ring. These new compounds, as well as their parent compound, 1,1-bis-(trifluoromethyl)-2,2diphenylethylene, are effective in preventing pregnancy in warmblooded animals and can be administered after coitus.

O United States Patent [151 3,678,l 1 7 Middleton July 18, 1972 [54] 1,l-BIS(TRIFLUOROlVIE'I'l'IYL)-2,2- References Cited DIPHENYLETHYLENES HAVING UNITED STATES PATENTS SELECTEDSUBSTITUENTS ON 3,237,200 2/l966 Baran et al. ..260/6l9 A X PHENYL y [72] Inventor: William J. Middleton, Chatham, Wilming- OTHER PUBLICATIONS ton, Del. Dixon, Jour. Org. Chem., Vol. 21 (1956) pages 400- 403 Assignee: E. I. du Pom de Nemours and p y, hl/gguel et al., Jour. Med. Chem, Vol. 6 (1963) pages 774- w'lmmgmni Middleton et al., Jour. Org. Chem., v01. 30 (1965) pages [22] Filed: Oct. 31, 1969 1,384- 1,389

Appl' 873124 Primary Examiner-Remand Helfin Anomey-James H. Ryan [52] US. Cl. ..260/619 R, 260/619 A, 260/613 R,

260/612 R, 260/570.7, 260/479 R, 260/468 R, ABSTRACT 260/479 Described are certain l,l-bis(trifluoromethyl)-2,2-diphen- 260/293.83, 260/ 93. 26 ylethylenes, which carry an oxy group in the para position of Int Cl Cmc 39/12 at least one benzene ring. These new compounds, as well as 58 Field of Search ..260/6l9 R, 619 A, 613 A Parent ylethylene, are efi'ective in preventing pregnancy in warmblooded animals and can be administered afier coitus.

2 Claims, No Drawings l l -BIS(TRIFLUOROMETI-IYL)-2,2- DIPI-IENYLETI-IYLENES HAVING SELECTED SUBSTITUENTS ON PI-IENYL BACKGROUND OF THE INVENTION This invention relates to novel l,l-bis( trifluoromethyl)-2,2- diphenylethylenes, wherein the para position of at least one benzene ring has an oxy group. This invention further relates to the use of these compounds in the prevention of pregnancy.

At present, there are widely used antifertility agents which act to establish a pseudopregnant condition in the female and thereby prevent ovulation. In general, they are mixtures of estrogens and progestins, and they must be taken daily during a major portion of the menstrual cycle. Unfortunately, administration of these mixtures can result in side effects similar to those commonly occurring during early pregnancy.

There is a need, however, for antifertility agents which can be administered after coitus and which do not have the undesirable pseudopregnancy side effects. I

SUMMARY OF THE INVENTION Now, according to this invention, it has been discovered that certain new l,l-bis(trifluoromethyl)-2,2-diphenylethylenes are effective antifertility agents for warm-blooded female animals when administered after coitus. It is probable that the mechanism of action is such that nidation is prevented. Compounds of this invention are easy to use and do not cause psuedopregnancy side effects.

The novel compounds are l,l-bis(trifluoromethyl)-2,2- diphenylethylenes (alternatively named 3,3,3-trifluoro-l,ldiphenyl-Z-trifluoromethylpropenes) having the formula in which X is H or OR; R being hydrogen, alkyl, hydroxyalkyl. aliphatic secondary aminoalkyl (including heterocyclic amine derivatives such as morpholinoalkyl, piperidinoalkyl and pyrrolidionalkyl) or an acyl group derived from an alkanoic, cycloalkanoic, cycloalkenoic, hydroxyalkanoic, dialkylaminoalkanoic or aromatic acid; the total carbon content of each R substituent not exceeding 12 carbon atoms.

DETAILED DESCRlPTlON OF THE INVENTION Representative R groups which are contemplated by this invention are: methyl ethyl, butyl, hexyl, octyl and dodecyl, including both straight chain and branched radicals; hydroxyethyl, hydroxypropyl, hydroxyhexyl, hydroxynonyl, dimethylaminomethyl, dimethylaminoethyl, diethylaminoethyl, dipropylaminobutyl, dibutylaminohexyl, N-morpholinoethyl, N-piperidinopropyl, Npyrrolidinomethyl, formyl, acetyl, propionyl, cyclohexanonyl, decanoyl. lactoyl, salicyl, diethylaminoacetyl, dimethylaminobutyryl, benzoyl. l-naphthoyl and 4-toluyl. The preferred compounds of this invention are those in which at least one of the R groups is hydrogen, a C,C alkyl group, or a C -C acyl group.

The diphenylethylenes in which X is hydrogen and R is alkyl can be prepared by the reaction of l,l-bis(tritluoromethyl)-2- fluoro-Z-phenylethylene with a p-alkoxyphenyllithium, as illustrated by the following equation.

The diphenylethylene in which R is H can be prepared similarly by the reaction of l,l-bis(trifluoromethyl)-2-fluoro- Z-phenylethylerie with the lithium salt of p-hydroxyphenyllithium, followed by acidification, as illustrated by the follow- 5 ing equation.

RO- CF:

01' with two equivalents of the lithium salt of p-hydroxyphenyllithium.

The diphenylethylenes in which the two phenyl rings contain non-identical OR groups can be prepared by the reaction of a l, 1 ,-bis( trifluoromethyl)-2-tluoro-2-p-alkoxyphenylethylene with a phenyllithium containing a different p-alkoxy group.

The l, l -bis(triflu0r0methyl )-2-fluoro-2-phenylethylenes used in these procedures can be prepared by the reaction of phenylmagnesium halide or p-alkoxyphenylmagnesium halide with perfluoroisobutylene, which is a well known compound described, i.e., in U. S. Pat. No. 2,6l7,836.

All of these reactions between the fluoroolefins and lithium compounds are conducted in the presence of an inert solvent such as diethyl ether or an aliphatic or aromatic hydrocarbon. The optimum reaction temperature is between 80 C. and +40 C., and the optimum pressure is between k and 3 atmospheres, the atmospheric pressure being the most convenient to employ. The products of the reaction can be isolated and purified by conventional techniques such as distillation, recrystallization, and chromatography.

The diphenylethylenes of this invention in which R is alkyl can also be made by first contacting hexafluorothioacetone with a p-alkoxy or a p,p-dialkoxydiphenyldiazomethane in an inert hydrocarbon, chlorohydrocarbon, or ether solvent at a temperature between 80 C. and +40 C. to form an episultide which next is thermally desulfurized at temperatures of about l00-250 C., as illustrated by the following equation.

EXAMPLE 1 1,l-Bis(trifluoromethy1)-2-pheny1- 2-(4-hydroxyphenyl)ethylene A solution of 13.84 g. (0.08 mole) of p-bromophenol in 100 ml. of ether was added dropwise to 0.16 mole of butyllithium in 200 ml. of 50/50 ether-hexane. The reaction mixture was stirred for 1 hour at room temperature, and then a solution of 20.8 g. (0.08 mole) of l-fluoro-2,2-bis(trifiuoromethyl)-1- phenylethylene in 25 ml. of ether was added dropwise over 15 min. The reaction mixture was stirred for 1 hour, then mixed with 200 ml. of 10% HCl. The ether layer was washed with water, dried (MgSOQ and distilled to give 7.1 g. ofa colorless liquid, b.p. l21125 (0.2 mm) that solidified on cooling. Recrystallization from pentane gave 6.5 g. of 1,1- bis(trifluromethyl)-2-phenyl-2-(4-hydroxyphenyl)-ethylene as colorless needles: mp 105-106 C.; F nmr (acetone) 8 54.7 (m,A B ir (KBr) 2.99 p. (OH); uv (ethanol) A 306 my. (6 9,900), 275 (5 10,200) and 232 (6 13,700).

Anal. Calcd. for c,,i-i,,,i=,o;

C, 57,84; H, 3.03; F, 34.32 Found: C, 57.97; H, 3.15;F, 34.21.

The 1-fluoro-2,2-bis(trifiu0r0methyl)-l-phenyl ethylene used in this example was prepared in the following manner:

Perfluoroisobutylene (68 ml. measured at 78 C. 0.6 mole) was slowly distilled over a period of 1.5 hours into a solution of 0.66 mole of commercial phenylmagnesium bromide in ether (440 ml.) cooled to 5-l0 C. Aqueous hydrochloric acid, 250 ml., was added, the organic layer separated, washed with water, and dried (MgSO Distillation gave 103 g. (67%) of 1fluoro-Z,2-bis(trifluoromethyl)-1- phenylethane as a colorless liquid: b.p. 84-85 C. (50 mm); 11,, 1.4179; ir (liquid) 5.98 (C C); uv (EtOH) A my (6 10,800); F nmr (neat) 6 56.6 ppm (d, 10 Hz to quartet, 8 Hz, eF), 59.0 ppm (d, 24 Hz, to quartet, 8 Hz, eF), 64.5 ppm (quartet, 24 Hz to quartet, 10 Hz, 1F).

Anal. Calcd. for C, H F,:

C,46.54; H, 1.95;F, 51.52 Found: C, 46.60; H, 2.18; F, 51.66.

EXAMPLE 2 1 ,1-Bis(trifluoromethyl)-2-pheny1-2- (4-acetoxyphenyl )ethylene X =H, R=acety1 A solution of 2.5 g. of 1,l-bis(trifluoromethyl)-2-phenyl-2- (4-hydroxyphenyl)ethylene in 10 m1. of acetic anhydride was heated at reflux for 2 hours. Water, 50 ml., was added to decompose the excess anhydride, and the solid that separated was collected on a filter, washed'with water, and recrystallized from pentane. There was obtained 2.3 g. of 1,1- bis(trifluoromethyl)-2-phenyl-2-(4-acetoxyphenyl)-ethylene as colorless crystals: m.p. 8486 C; F nmr (CCl F) 8 55.7 ppm (s); H nmr (CCl F) -r 2.6-3.0 (m, 9H) and 'r 7.89 (m, CH ir (KBr) 5.62 p. (C O); uv (ethanol A 262 my. (6 10,600) and 221 (5 14,600).

Anal. Calcd. for c,,,H,,F.,o,;

C, 57.76; H, 3.23; F, 30.46 Found: C, 57.50; H, 3.49; F, 30.52.

EXAMPLE 3 1,1-Bis(trifluoromethyl)-2,2-di( 4-ethoxyphenyl)ethylene X OR, R ethyl An 80.4 g. sample (0.4 mole) of p-bromophenetole was added dropwise to a solution of 0.4 mole butyllithium in 500 ml. of 50/50 ether-hexane. The reaction mixture was stirred at room temperature for 1 hour, and then cooled in an ice bath. Perfluoroisobutylene, 25 ml. measured at 78 C. was slowly distilled into the reaction mixture over a period of 30 minutes. Aqueous 10 percent hydrochloric acid, 200 ml., was added and the organic layer was separated, washed with water, dried (MgSO and distilled to give 40 g. ofa colorless liquid, b.p. 148158 C. (0.2 mm.) that solidified upon cooling. Recrystallization from pentane gave 30.1 g. of 1,1- bis(trifluoromethyl)-2,2-di(4-ethoxyphenyl)ethylene as colorless crystals: m.p. 71-73 C.; F nmr (CCl -,F) 8 55.3 ppm (5); H nmr (CCl F) r 3.13 (m, A 8 8H), 1- 6.05 (quartet, .1 7H2, 4H) and 1' 8.65 (I, L] 7H2, 6H); uv (ethanol A 300 mu (6 18,600) and 229 my. (6 18,300).

Anal. Calcd. for C H F O C, 59.41; H, 4.49; F, 28.19 Found: C, 59.48; H, 4.62; F, 28.12.

EXAMPLE 4 l ,1-Bis(trifluoromethy1)-2,2-di(4-methoxyphenyl )ethylene X OR, R methyl 4-Bromoanisole, 20.6 g. (0.11 mole) was added dropwise over 20 min. to 0.1 mole of butyllithium in 60 ml. of hexane solution, and the reaction mixture was stirred for 30 min. A 50 m1. portion of ether was added to bring the precipitated solids into solution, and then 23 g. (0.08 mole) of l-fluoro-2,2- bis(trifluoromethyl)-l(4-methoxy-phenyl)ethylene was added dropwise over 30 min. Cooling was maintained to keep the temperature between 2540 C. Aqueous 10% hydrochloric acid, 100 ml., was added and the organic layer was separated, washed with water, and dried (MgSO,). Distillation gave 16.5 g. (55%) of l,l-bis(tri-fluoromethyl)-2,2-di(4-methoxyphenyl)ethylene as a viscous liquid, b.p. l30-l34 C.(0.06 mm), that crystallized in pentane to give colorless needles:

m.p. 77-78; F nmr (CCl F) 55.3 ppm (s); H nmr (CCl F) 1- 6.28 (s, 6H) and r 3.07 (m, 8H); and uv (EtOH) A 229 mp. (5 18,300), 229 m (6 17,000).

Anal. Calcd. for C H F O C, 57.45; H, 3.75; F, 30.30.

Found: C, 57.66; H, 3.66; F, 30.25.

Deep purple solutions are formed when this material is dissolved in strong acids such as trifluoroacetic acid or 60 percent sulfuric acid. The spectral evidence of a solution in 98 percent sulfuric acid indicates that a stable carbonium ion is formed:

F nmr (98% H 50 8 59.7 ppm (d, J 7.7 Hz); uv (98% H SO,) 545 mu (6 40,200), 345 mp. (6 9,580) and my. (6 8,000).

The l-fluoro-2,2-bis(trifluoromethyl)-l(4-methoxyphenyl)ethylene used in this example was prepared in the following manner:

A 56.12 g. sample (0.3 mole) of p-bromoanisole was added dropwise to 8.00 g. (0.33 mole) of magnesium turnings in 500 ml. of ether. Grignard formation was complete in'about 2 hours. The solution was cooled to l5-20 C. 34 ml. (ca. 0.3 mole) of perfluoroisobutylene was distilled into the solution over a period of 30 min., and then 200 ml. of aqueous percent hydrochloric acid was added. The ether layer was separated, washed with water, dried (MgSO and then distilled. There was obtained 56.5 g. (65%) of l-fluoro-2,2- bis(trifluoromethyl)-l-(4-methoxyphenyl)ethylene as a colorless liquid: b.p. 8l82 C. (5.2 mm); n 1.4534; lr (liquid) 6.18 p. (C CF); uv (EtOH) A 282 mp. (e 14,900), 218 mp. (6 9,730); F nmr (neat) 6 56.4 (quartet J 8.5 Hz to d,J 10 Hz, 3F), 58.7 (quartet .I 8.5 Hz to d, J 24 Hz, 3F), 64.9 (m, 1F). Anal. Calcd. for C,,H F,O: C, 45.85; H, 2.45; F, 46.15.

Found: C, 46.15; H, 2.50; F, 46.42.

EXAMPLE 5 1,1 -Bis(trifluoromethyl )-2( 4-methoxyphenyl)-2-phenylethylene x H, R methyl A solution of 22.6 g. (0.1 mole) of 4-methoxybenzophenone hydrazon e in 100 ml. of methylene chloride 0 was added dropwise over a period of one hour to a stirred suspension of 23.2 g. (0.1 mole) of silver oxide in 50 m1. of methylene chloride cooled in an ice bath. The reaction mixture was stirred for 2 hours, 20 g. of magnesium sulfate was added, and the stirring was continued for 20 minutes. Filtration gave a dark purple solution of the diazo compound.

CHI? C]H;0

s /C F3 0N; org-d4. c =c Q o F;

Hexafluorothioacetone was added portionwise to this solu- ,tion of phenyl-4-methoxyphenyldiazomethane in methylene chloride cooled to C. until the purple solution faded to yellow. The solvent was removed by evaporation, and the residue was redissolved in pentane. The pentanc solution was filtered to remove the sulfur, and the filtrate was distilled. There was obtained 7.2 g. of l,l-bis(trifluoromethyl)-2-(4- methoxyphenyl)-2-ethylene as a nearly colorless liquid, b.p. 102103 C. (0.2 mm), n 1.5266. The F nmr (CCIF showed a multiplet (87 percent integrated area) at 55.4 ppm from CClF and absorptions 13 percent tota1)due to impurities at 61.1, 64.6, and 64.8 ppm. Anal. Calcd. for C H F O: C. 58.96; H, 3.50; F, 32.92.

Found: C, 60.04; H, 3.87; F, 30.08.

EXAMPLE 6 l, l -Bis(trifluoromethyl )-2-phenyl-2- [4-(B-diethylamino )ethoxyphenyl ethylene citrate X H, R diethylaminoethyl Nao-\ c F;

(C7l{5)zNCH2CH20l C:

A 0.85 g. sample (0.007 mole) of Brchlorotriethylamine was added to a solution of 1.66 g. (0.005 mole) of 1,1- bis( trifluoromethyl l -phenyll 4-hydroxyphenyl )ethylene in aqueous 5 percent sodium hydroxide. The oil that precipitated was collected in 75 ml. of ether, and the ether extract was dried over sodium hydroxide pellets and then mixed with a solution of 1.1 g. (0.005 mole) of citric acid in 200 ml. of wet ether. The precipitate that formed was collected on a filter, washed with ether, and dried in air to give 1.6 g. of a white powder. Recrystallization from acetone gave 1.1 g. of l, l -bis(triiluoromethyl )-2- phenyl-2-[ 4-( B-diethylamino)ethoxyphenyl]ethylene citrate as colorless crystals; m.p. l34l36 C.; F' nmr (acetone-d6) 8 54.1 ppm (multiplet, CF

Anal. Ca1cd.'for C H F NO Table l Cbminued Reactants 1,1-bis(trifiuormethyl) -2-phenyl-'2-(p-Q-cycloliexenylcarbonyloxyphenyDethylemzHmNcHiooon 1,l-bis(tritluoromethyl)-2-pl1enyl-2-(p-diethylaniinoacetoxypllenylmtliylom-.

The new compounds of this invention, as well as their parent compound, 1, 1 -bis( trifluoromethyl )2,2-diphenylethylene, are useful in prevention of pregnancy in warm blooded animals. The compounds can be administered by any suitable means. Oral administration is preferred. Administration also can be parenteral, that is subcutaneous or intramuscular, or rectal. The compounds are preferably administered in a single dose, preferably orally, after coitus, but before implantation of the fertilized egg. Alternatively, single or divided doses can be administered daily during all or a substantial fraction of the estrous cycle or menstrual cycle.

Doses will ordinarily range from about 0.0005 to about 50 milligrams per kilogram of body weight of the recipient per day (mg./kg.-day). The preferred dosage range is from about 0.0025 to about mg./kg.-day, and the most preferred range is from about 0.005 to about 5 mg./kg.-day.

.These compounds can be employed with satisfactory results to prevent pregnancy in laboratory animals such as rats, mice, guinea pigs, rabbits, monkeys and chimpanzees and are also effective in preventing pregnancy in domestic animals such as swine, cows, sheep and horses. In small animals it is usually convenient to administer them in the form of a capsule, or incorporate them in the animal feed. For large animals,

parenteral administration is often preferred;

These compounds can be employed in useful compositions in such dosage forms as tablets, capsules, powder packets, or liquid solutions, suspensions, or elixirs for oral administration or liquid solutions for parenteral use, andin certain cases, suspensions for parenteral use. In such compositions, the active ingredient will ordinarily always be present in the amount of at least 0.01 percent by weight based on the total weight of the composition and not more than 90 percent by weight.

Besides the active l,l-bis(trifluoromethyl)-2,2-diphenylethylenes, the composition will contain a solid or liquid nontoxic pharmaceutical carrierfor'the active ingredient.

In one embodiment of a pharmaceutical composition of this invention, the solid carrier is a capsule which can be of the ordinary gelatin type. The capsule will contain from about 0.03-75 percent by weight of the active compound and 99.97-25 percent of a carrier.

In another embodiment, the active ingredient is tableted with or without adjuvants. In yet another embodiment, the active ingredient is put into powder packets. These capsules,

tablets and powders will usually contain about 0.03 to 95 percent and preferably 0.1 to 70 percent by weight of active ingredient. These dosage forms preferably contain about 0.1 to 700 milligrams of active ingredient, a quantity of about 0.03 milligram to 350 milligrams being most preferred.

The pharmaceutical carrier can be a sterile liquid such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like. In general, water, saline, aqueous dextrose (glucose) and related sugar solutions, and glycols such as propylene glycol or polyethylene glycols are preferred liquid carriers, particularly for injectable solutions. Sterile injectable solutions, such as saline, will ordinarily contain about 0.0035 to 25 percent, and preferably about 0.01 to 5 percent by weight of the active ingredient.

Suitable formulations for oral administration can be prepared in a suspension, syrup or elixir in which the active ingredient ordinarily will constitute about 0.0007 to 5 percent and preferably about 0.003 to 1 percent by weight. The pharmaceutical carrier in such composition can be an aqueous vehicle such as an aromatic water, a syrup or a pharmaceutical mucilage.

Suitable pharmaceutical carriers are described in "Remingt'ons Pharmaceutical Sciences" by E. W. Martin, a wellknown reference text in this field.

The following examples further illustrate the fertility control in warm-blooded animals by the process of the present inventron.

EXAMPLE A Immature female rats (28 days old) are induced into precocious puberty with a single dose of pregnant mares serum gonadotrophm and then are mated with normal males. 1,1-

Bis(trifluorometh'yl(-2,2-di(4-methoxyphenyl)ethylene (the product of Example 4) suspended in sesame oil is orally administered in graded doses to numerically equal groups of these female rats for 6 days starting on the day of finding sperm or a vaginal plug. One week after mating, the animals are killed and their uteri are examined for implantation sites. If any are found, the animal is considered pregnant. Control animals have a mean of eight implantation sites. The dose level at which 50 percent of the animals show no evidence of pregnancy, the ED is 0.08 mg./kg.-day.

The general procedure of the preceding example is repeated with other bis(trifluoromethyl)diphenylethylenes. Table II summarizes these experiments.

. TABLE 11 Compound of Example ED in mg./l-:g.-da

When the parent compound, l,l-bis(trifluor0methyl)-2,2-

diphenyle'thylene, was used in a similar experiment, it had an in which X is selected from H and OR; and R is hydrogen.

2. l,1-Bis(trifluoromethyl)-2-phenyl-2-(4-hydroxyphenyl)ethylene, the compound of claim I in which each of X and R isl-I.

2 3 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION 3 57 17 Dated Jul} 18, 197

Patent No.

Invent r( William J. Middleton It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

F Col. 2, at about line 7, the formula Li Q OLl should be LiQOLi 001. L line 2'7, "H nmr" should be H' nmr line 29, "(C 0)" should be (0:0) line 63, "H nmr" should be H' nmr Col. 5, line 63, "(0 CF)" should be (C=CF) Col. 6, line 1, delete the single bond between the benzene ring and A 5 0;

Signed and sealed this 6th day of February 1973.

(SEAL) Attest:

EDWARD M.FLETCBER,J'R. ROBERT GUTI'SCHALK Attesting Officer Commissioner of Patents 

2. 1,1-Bis(trifluoromethyl)-2-phenyl-2-(4-hydroxyphenyl)ethylene, the compound of claim 1 in which each of X and R is H. 